ABSTRACT
Three zinc metallopeptidases are implicated in the regulation of fluid homeostasis and vascular tone and represent interesting targets for the treatment of chronic heart failure. We have previously reported the synthesis of a triple inhibitor able to simultaneously inhibit neprilysin (NEP, EC 3.4.24.11), angiotensin-converting enzyme (ACE, EC 3.4.15.1) and endothelin-converting enzyme (ECE-1, EC 3.4.24.71) with nanomolar potency towards NEP and ACE and a lesser affinity for ECE. Here, we report the optimization and biological activities of analogs derived from lead compound 1 (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3- (1H-indol-3-yl)-propionic acid by a structural approach. Among several inhibitors, compound 21, (2S)-2-[(2R)-2-((1S)-5-bromo-indan-1-yl)-3-mercapto-propionylamino]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid was selected by taking into account its good molecular adaptation with the recently published structures of the three vasopeptidases. This optimization procedure led to an improved pharmacologic activity when compared with 1.
Subject(s)
Alanine/chemistry , Alanine/pharmacology , Angiotensin-Converting Enzyme Inhibitors/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Indans/chemistry , Indans/pharmacology , Neprilysin/antagonists & inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Tryptophan/analogs & derivatives , Alanine/analogs & derivatives , Alanine/chemical synthesis , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Endothelin-Converting Enzymes , Indans/chemical synthesis , Male , Metalloendopeptidases/antagonists & inhibitors , Metalloendopeptidases/metabolism , Molecular Structure , Peptidyl-Dipeptidase A/metabolism , Protease Inhibitors/chemical synthesis , Rats , Rats, Wistar , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Tryptophan/chemistry , Vascular Diseases/therapyABSTRACT
Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is the penultimate enzyme in melatonin (5-methoxy-N-acetyltryptamine) biosynthesis. It is the key-enzyme responsible of the nocturnal rhythm of melatonin production in the pineal gland. Specific AANAT inhibitors could be useful for treatment of different physiopathological disorders encountered in diseases such as seasonal affective disorders or obesity. On the basis of previous works and 3D-QSAR studies carried out in our laboratory, we have synthesized and evaluated four novel benzo[b]thiophene derivatives designed as AANAT inhibitors. Compound 13 exhibited high inhibitory activity (IC50 = 1.4 microM) and low affinities for both MT, (1100 nM) and MT2 (1400 nM) receptors.
Subject(s)
Arylamine N-Acetyltransferase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors , Thiophenes , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Quantitative Structure-Activity Relationship , Receptor, Melatonin, MT1/metabolism , Receptor, Melatonin, MT2/metabolism , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
Serotonin N-acetyltransferase (arylalkylamine N-acetyl-transferase, AANAT) is an enzyme that catalyses the first rate limiting step in the biosynthesis of melatonin (5-methoxy-N-acetyltryptamine). Different physiopathological disorders in human may be due to abnormal secretion of melatonin leading to an inappropriate exposure of melatonin receptors to melatonin. For that reason, we have designed, synthesized and evaluated as inhibitors of human serotonin N-acetyltransferase, a series of compounds that were able to react with coenzyme A to give a bisubstrate analog inhibitor. Compound 12d was found to be a potent AANAT inhibitor (IC50 = 0.18 microM).
Subject(s)
Arylamine N-Acetyltransferase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Databases, Factual , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
Conformationally restricted phenalene and acenaphthene derivatives 5 were synthesized from phenalen-1-one and acenaphthen-1-one derivatives using the Horner-Emmons reaction. The amines were prepared through the corresponding isocyanates by the Curtius reaction on the acids or by the reduction of the nitriles. Amido derivatives (R(3) = Me, Et, n-Pr, c-Pr) were prepared by acylation of the amines with the appropriate anhydrides or acid chlorides or by the reductive acylation of the nitriles. The affinities of the compounds for melatonin binding sites were evaluated in vitro in binding assays using chicken brain melatonin and the human mt(1) and MT(2) receptors expressed in HEK-293 cells. The functionality of the compounds was determined by the potency to lighten the skin of Xenopus laevis tadpoles. Highly potent compounds were obtained. The data highlighted the role of the methoxy group located in the ortho position to the ethylamido chain as compounds with picomolar affinities such as 14c were obtained (chicken brain, hmt(1), hMT(2) K(i) values = 0.02, 0.008, 0.069 nM, respectively). Compound 14c was equipotent to the corresponding dimethoxy derivative 15c (chicken brain, hmt(1), hMT(2) K(i) values = 0.07, 0.016, 0.1 nM, respectively). On the other hand, the restricted conformation of the amido chain did not influence selectivity for the cloned hmt(1) and hMT(2) receptors. These compounds were also potent agonists of melanophore aggregation in X. laevis. 15a,c were several hundred fold more potent than melatonin (EC(50) = 0.025, 0.004 nM, respectively). Conformational studies indicated that the minimum energy folded conformation of the ethylamido chain could constitute the putative active form in the receptor site in agreement with previous results.
Subject(s)
Acenaphthenes/chemical synthesis , Receptors, Cell Surface/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Acenaphthenes/chemistry , Acenaphthenes/pharmacology , Animals , Binding, Competitive , Brain/metabolism , Cell Line , Chickens , Female , Humans , In Vitro Techniques , Larva , Ligands , Male , Models, Molecular , Pigmentation , Receptors, Melatonin , Skin/drug effects , Stereoisomerism , Structure-Activity Relationship , Xenopus laevisABSTRACT
A new series of substituted oxygenated heterocycles and thio-analogues were synthesized and evaluated as melatonin receptor ligands. The replacement of the indolic moiety of melatonin by heterocyclic skeleton such as 1,4-benzodioxin, 2,3-dihydro-1,4-benzodioxin, chroman, 2,3-dihydro-1,4-benzoxathiin, thiochroman, carrying the amidic chain on the aromatic ring, leads to compounds showing a weak affinity for melatonin receptors, except for the compounds 1cb and 1hb.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Melatonin/metabolism , Oxygen/chemistry , Animals , Chickens , Evaluation Studies as Topic , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/metabolism , Heterocyclic Compounds/pharmacology , Ligands , Magnetic Resonance Spectroscopy , SwineABSTRACT
Tetrahydronaphthalenic ligands were synthesized and evaluated as melatonin receptor ligands. Biological studies show that the aromaticity of the ring bearing the side chain is not essential for affinity and activity and that replacement of the methoxy group with the bioisostere ethyl which does not offer the possibility of H-bonding, leads to antagonist or forskoline potentiating properties.
